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WORKWEEK 2015
10-12 May 2015
Eindhoven, the Netherlands
This booklet has been kindly sponsored by
Stratingh Institute for Chemistry
Rijksuniversiteit Groningen
Workweek Eindhoven 2015
Hirsch group
Minnaard group
Otto group
Roelfes group
Witte group
Dear participants,
Welcome to Stratingh Workweek 2015!
In this booklet you can find the 3-day program for the workweek with details
regarding schedules and activities and also the symposium program, detailing
presentations and poster abstracts.
We acknowledge all our sponsors for their generous contributions and helping us
in making this workweek possible.
We wish you a very enjoyable and inspiring workweek…and don’t forget to
have fun!
Best regards,
The Workweek Committee 2015
Yiğit, Meniz and Ruben
FEI Company
With more than 60 years of innovation and leadership, FEI enables customers to
find meaningful answers to questions that accelerate breakthrough discoveries,
increase productivity, and ultimately change the world.
FEI designs, manufactures, and supports the broadest range of high-performance
microscopy workflows that provide images and answers in the micro-, nano-,
and picometer scales.
Combining hardware and software expertise in electron, ion, and light
microscopy with deep application knowledge in the materials science, life sciences, electronics, and natural resources markets, the worldwide FEI team of
2,700+ employees is dedicated to customers' pursuit of discovery and resolution
to global challenges.
THIS IS SABIC
Program
Wednesday, 10th of June
07:00
Meeting at “AH to go” in front of the Bernoulliborg
10.30
Arrival at FEI Company, Eindhoven
10.30 - 13.00 Visit at FEI Company (including lunch)
13.00
Departure to High Tech campus Eindhoven
13.30 - 13:50 Welcome - Registration
13.50 – 17:40 Scientific program
17.40 – 18:45 Check-in to Sandton Hotel Eindhoven
19.00
Dinner at Dzjengis Khan
Program
Thursday, 11th of June
07.00-08.30
Breakfast at the hotel
08.30
Departure from hotel
09.00 - 13.00 Scientific program
12.40 - 14.00 Lunch at De Zwarte Doos
14.00 - 18.00 Scientific program
18.00 - 18.30 Free time
18.30 - 20.30 Dinner at The Trafalgar pub
20.30 - - -
Bonte avond
Program
Friday, 12th of June
07.00 - 09.45 Breakfast at the hotel
10.00
Departure from hotel
11.00
Arrival at activity
11.00 - 16.00 Activity (including lunch)
16.00
Departure from activity to Groningen
20.00
Arrival at Groningen
Activity
A walking experience
for young and old.
The bare feet walking barefoot on
the path is a challenge to nature
in a different way
to know. It is healthy,
challenging and fun!
Over a range of 4 kilometers you walk on different
surfaces of moss, forest, gravel, coal, sand, wood,
bark, soil particles, water and mud, you feel hot and
cold, wet and dry. Let your feet massaged by nature!
You will also find games on your foot path.
There is also the Celtic forest with a labyrinth,
triad and an endless circle. While enjoying a real
dream pond where you can relax or paddle in
the water.
4000 years of experience.
Walking barefoot over different surfaces has an effect which actually is on foot
reflexology.
Foot reflexology has been 4,000 years old and is originally from India and
China.
By walking barefoot stimulates 30,000 nerve endings that are under foot.
Walking through mud and water also gives a supposedly kneipeffect.
The feet are again flexible. After walking barefoot to experience more energy
flowing
through your body. The unique experience of nature and the direct contact with
the
clay relaxing and stimulating mind and body.
Addresses and other information
Company visits
FEI Company
Achtseweg Noord 5, 5651GG Eindhoven, The Netherlands
Hotel
Sandton Eindhoven Centre
Stratumsedijk 23D, 5611NA Eindhoven, The Netherlands
Symposium
Eindhoven University of Technology
Ceres Building
High Tech campus, Eindhoven, The Netherlands
Restaurants
Dinner (Wednesday, 10th of June)
Dzjengis Khan
Aalsterweg 99A, 5615CC Eindhoven, The Netherlands
Lunch (Thursday, 11th of June)
De Zwarte Doos
Den Dolech 2, 5612AZ Eindhoven, The Netherlands
Dinner (Thursday, 11th of June)
The Trafalgar pub
Dommelstraat 21, 5611CJ Eindhoven, The Netherlands
The Stratingh Institute for Chemistry
@
Technische Universiteit Eindhoven
Symposium Program
10th and 11th June 2015
Dear participants,
We are very pleased to present you the program of the joint symposium
between the Stratingh Institute for Chemistry of the Rijksuniversiteit Groningen
and the departments of chemistry of the Eindhoven University of Technology.
It has been a long-standing tradition of the Stratingh Institute to visit a wellreputed academic institution every year and actively participate in exchange. We
are very happy that the departments of Chemistry of the Eindhoven University
of Technology has welcomed us and are co-organizing this joint symposium.
For all of us this symposium is an important occasion to meet other young
scientists and interact with them on a scientific and a social level. It is also an
excellent opportunity for PhD students to present their work and gain valuable
experience and insights. We hope that the diversity of topics presented today
will allow everyone to have helpful and inspiring discussions.
We acknowledge all our sponsors for helping us to realize this symposium. All
logos and adverts of the various sponsors can be found in the booklet.
We wish you a very nice and inspiring symposium.
The Workweek Committee 2015
Yiğit Altay
Meniz Tezcan
Ruben Maaskant
Program
13.30-13.50 Welcome – registration
13.50 – 15.40 Session 1
13.50-14.00 Opening
14.00-14.40 Prof. Bert Meijer – Eindhoven University of Technology
“Non-covalent synthesis of functional supramolecular systems”
14.40-15.10 Lara Villarino – University of Groningen
“Supramolecular Assembly of Artificial Metalloenzymes for
Enantioselective Protonation”
15.10-15.40 Stijn Aper – Eindhoven University of Technology
“Light- and small-molecule responsive Zn2+ protein switches”
15.40-16.00 Coffee break
16.00 – 17.40 Session 2
16.00-16.40 Gerard Roelfes – University of Groningen
16.40-17.10 Mannathan Subramanyan – University of Groningen
“Palladium-Catalyzed Conjugate Addition of Aryl iodides to
Activated Alkenes”
17.10-17.40 Jessica Clough – Eindhoven University of Technology
“Illuminating the mechanomemory of a filled elastomer”
09.00 – 10.40 Session 3
09.00-09.40 Sijbren Otto – University of Groningen
09.40-10.10 Niek Eisink – University of Groningen
“Selective Modification Of Unprotected Oligosaccharides”
10.10-10.40 Jonas Lohse – University of Groningen
“Targeted diazo transfer probes”
10.40-11.00 Coffee break
11.00 – 12.40 Session 4
11.00-11.40 Maarten Merkx – Eindhoven University of Technology
11.40-12.10 Bas van Genabeek – Eindhoven University of Technology
“Monodisperse oDMS-oLA block co-oligomers: Working on the limits of block
copolymer synthesis and self-assembly”
12.10-12.40 Yagiz Ünver – University of Groningen
“Fragment Linking of Inhibitors of the Aspartic Protease Endothiapepsin
Facilitated by Protein-Templated Click Chemistry”
12.40-14.00 Lunch
14.00 – 15.40 Session 5
14.00-14.40 Rint Sijbesma – Eindhoven University of Technology
14.40-15.10 Ivica Cvrtila – University of Groningen
“Acyl hydrazone based dynamic combinatorial libraries
responsive to UV irradiation”
15.10-15.40 Daan van der Zwaag – Eindhoven University of Technology
“Analyzing dynamics in supramolecular polymers”
15.40-17.30 Poster session
17.30-18.00 Closing – poster prize announcement
Map high tech campus and lunch
Lunch
Registration & Poster session – CERES building
Lectures – CERES building
Presentation Abstracts
Supramolecular Assembly of Artificial Metalloenzymes for
Enantioselective Protonation
Lara Villarino Palmaz, Gerard Roelfes
Lara Villarino Palmaz, Stratingh Institute for Chemistry, Nijenborgh 4, Groningen, 9747AG,
The Netherlands
[email protected]
Artificial metalloenzymes are hybrid catalysts in which a catalytically active transition metal
complex is incorporated into a host biomacromolecule, typically a protein or DNA. The aim is
combine the best of both worlds, that is, broad catalytic scope, a hallmark of homogeneous
catalysis, and high activity and selectivity under mild conditions, which typically characterizes
enzymatic catalysis.[1]
The key parameter in artificial metalloenzymes design is the second coordination sphere
provided by the biomolecular scaffold. The Roelfes group developed a novel concept for the
creation of artificial metalloenzymes, which involves the creation of an active site in the dimer
interface of the transcription factor “Lactococcal multidrug resistance Regulator” (LmrR). A
copper(II)-phenantroline complex was anchored in the hydrophobic pocket of the protein
using a cysteine conjugation strategy. This new metalloenzyme was successfully employed
in the catalytic asymmetric Diels-Alder reaction, with up to 97% ee, [2] and in the conjugate
addition of water, with up to 84% ee.[3]
Supramolecular assembly of the transition metal complex is very attractive, since the hybrid
catalyst is prepared by self-assembly. Thus, there is no need for chemical modification and
subsequent purification steps, which greatly facilitates the discovery, optimization and
application of novel artificial metalloenzymes. Herein, we present the supramolecular
assembly of a novel artificial metalloenzyme based on LmrR and its application in a highly
challenging reaction: the tandem Friedel Crafts/Enantioselective protonation in water
(Scheme 1). [4]
Scheme 1
References:
[1] F. Rosati, G. Roelfes, ChemCatChem, 2010, 2, 916-927.
[2] J. Bos, F. Fusetti, A. J. M. Driessen, G. Roelfes, Angew. Chem. Int. Ed, 2012, 51, 7472-7475.
[3] J. Bos, A. García-Herraiz, G. Roelfes, Chem. Sci., 2013, 4, 7472-7475.
[4] J. T. Mohr, A. Hong, B. M. Stoltz, Nature Chem., 2009, 1, 359-369.
Light- and small-molecule responsive Zn2+ protein switches
Stijn Aper, Andy van Vroenhoven, Maarten Merkx
Eindhoven University of Technology, Department of Biomedical Engineering, Laboratory of
Chemical Biology
[email protected]
Zn2+ plays an important catalytic and structural role in many fundamental cellular processes
and its homeostasis is tightly controlled. Dysregulation or deficiency of Zn2+ has been related
to diseases including neurodegeneration, growth retardation, immunodeficiency, cancer and
diabetes. Genetically-encoded FRET-sensors, for example the eCALWY series developed in
our group, have allowed us to image Zn2+ levels in human cells. Recently, free Zn2+ has also
been suggested to act as an intracellular signaling molecule. To get increased understanding
of this signaling role, tools are required to perturb the intracellular Zn2+ concentration. We
have developed two types of genetically-encoded, modular protein switches for this
application, one using light as input and the other employing small-molecule regulation.
The light-responsive protein switch consists of two light-responsive Vivid domains and
the Zn2+ binding domains Atox1 and WD4, linked together with flexible peptide linkers. In the
dark, Zn2+ is tightly bound in between the two Zn2+ binding proteins. Light-induced
dimerization of the Vivid proteins disrupts this interaction and thus results in Zn2+ release. For
the initial design we obtained a 3-fold decrease in Zn2+ affinity going from dark- to light-state,
which was further improved to 10-fold by optimizing the linkers between the protein domains.
In addition, the Zn2+ affinities of both states and the dark-state reversion kinetics have been
tuned.
The small-molecule responsive protein switch employs the fusicoccin-regulatable
interaction between the tobacco 14-3-3 protein and the C-terminus (CT) of the H+-ATPase
PMA2, to control Zn2+ binding between coordinating amino acids residing on two fluorescent
proteins. All input and output domains are linked together via flexible peptide linkers. Upon
addition of the small-molecule fusicoccin the interaction between the 14-3-3 protein and CT
is significantly enhanced, which weakens the Zn2+ binding between the coordinating proteins.
After tuning of the interaction between 14-3-3 and CT, we obtained a fusicoccin-induced 20fold decrease in Zn2+ affinity. We are currently assessing the performance of both light- and
small-molecule responsive Zn2+ protein switches in mammalian cells.
Palladium-Catalyzed Conjugate Addition of Aryl iodides to
Activated Alkenes
Subramaniyan Mannathan, Johannes G. de Vries,* Adriaan J. Minnaard*
Subramaniyan Mannathan, Stratingh Institute for Chemistry, Nijenborgh 7, 9747 AG
Groningen
[email protected]
Abstract- Transition-metal catalyzed conjugate addition of organometallic reagents to
activated alkenes is one of the efficient methods to form C-C bonds in organic synthesis. A
variety of organometallic reagents such as organoboron, -zinc, -aluminium, -silicon, and
magnesium (Grignard) reagents have been used and these strategies are well documented.
On the other hand, application of aryl iodides in these types of reactions has been rarely
studied. Herein, we present a palladium catalyzed conjugate addition of aryl iodides to
activated alkenes [1]. As compared to our previously reported effective Pd(0)-NHC catalyst
system [2], this method provides an opportunity to use a relatively inexpensive palladium
catalyst with similar efficacy.
R2
I
R1
EWG
1 mol% Pd(OAc) 2
DIPEA (5.0 equiv)
NMP, 80 °C, 6 h
R1
EWG
R2
upto 80% yield
R1
R2
= Aryl, alkyl
EWG = COR, NO 2
= OMe, Cl, F, CF 3
12 examples
After careful optimization of the reaction conditions, various activated alkenes have been
examined. Enones are the most effective substrates affording 1,4-addition products in good
yields. Interestingly, β-nitrostyrenes also work well, furnishing the conjugate addition
products in moderate yield. On the other hand, reactions with acrylates and unsaturated
nitriles, give solely the corresponding Heck products. A variety of aryl iodides has been
applied to give the corresponding 1,4-addition products in good yield.
References:
[1]
[2]
S. Cacchi, A. Arcadi, J. Org. Chem. 1983, 48, 4236–4240
A. L. Gottumukkala, J. G. de Vries, A. J. Minnaard, Chem. Eur. J. 2011, 17, 3091–3095.
Illuminating the mechanomemory of a filled elastomer
Jessica M. Clough,1 Stephen L. Craig,2 Rint P. Sijbesma1
(1) Department of Chemistry and Chemical Engineering, Eindhoven University of
Technology, 5612 AZ Eindhoven, The Netherlands
(2) Department of Chemistry, Duke University, Durham, NC 27708, United States
[email protected], [email protected]
Dioxetane mechanoluminescence, first demonstrated in our group in 2012,1 is a powerful
new way of visualizing stress distributions in polymeric materials.2,3 In recent work, we use
mechanoluminescence to interrogate the microscopic origins of the unique mechanical
properties of elastomers. These ubiquitous engineering materials are found in many
applications where high tensile strength, deformability and toughness are required, but these
remarkable properties can only be obtained from the addition of large amounts of
nanoparticles, or fillers.4 Cyclic uniaxial tensile testing on dioxetane-functionalised silicafilled poly(dimethylsiloxane) (PDMS) shows that covalent bond scission is an important
contributor to the observed mechanical behaviour only above a certain strain threshold
(>130%) and becomes increasingly important with the degree of permanent deformation. The
mechanomemory of PDMS can also be visualised with mechanoluminescence: light
emission is observed only when the material experiences a new strain. Lastly, straining preconditioned samples at different orientations relative to the original tensile direction also
reveals a strong anisotropy in the strain-induced covalent scission.
Stress/ MPa
Light intensity/ arbitrary
units
3.5
2.5
1.5
0.5
-0.5
0
50
100
150
200
Strain/ %
Stress-strain behaviour of PDMS on cyclic loading (black), overlaid with resulting
mechanoluminescence emission (blue). Cyclic uniaxial tension testing performed with Zwick
instrument in the Department of Mechanical Engineering. Mechanoluminescence recorded at 10 fps
and 95 ms exposure time with sCMOS camera (PCO 5.2)
References:
(1) Y. Chen, A. J. H. Spiering, S. Karthikeyan, G. W. M. Peters, E. W. Meijer, R. P. Sijbesma Nat.
Chem. 2012, 4, 559-562
(2) Y. Chen, R. P. Sijbesma Macromolecules 2014, 47, 3797-3805
(3) E. Ducrot, Y. Chen, M. Bulters, R. P. Sijbesma, C. Creton Science 2014, 344, 186-189
(4) J. Diani, B. Fayolle, P. Gilormini Eur. Polym. J. 2009, 4, 601-612
!
SELECTIVE MODIFICATION OF UNPROTECTED OLIGOSACCHARIDES
Niek N. H. M. Eisink [a], Martin D. Witte
[a]
, Adriaan J. Minnaard
[a]
!
[a]
Niek Eisink, Stratingh Institute for Chemistry, University of Groningen Nijenborgh 7, 9747 AG,
Groningen (The Netherlands), [email protected]
Selective modification of unprotected carbohydrates is a relatively unexplored area, with the exception
of the modification of the primary hydroxyl group and the anomeric center. Such modifications on
oligosaccharides are scarce and furthermore seldom involve one of the secondary hydroxyl groups. In
the field of chemical biology, where often more complex carbohydrates are employed, selective
modifications are highly desired. Recently, in our group we have developed an effective procedure for
the regioselective oxidation of mono- and disaccharides.1 With this method, we can selectively oxidize
the C3 hydroxyl group on the terminal glucose residue in maltose and cellobiose. The formed ketone
moeity opens up a whole range of further modifications of these carbohydrates. We envisioned that we
could apply the same method to modify higher oligosaccharides. A boundry in applying our method for
oligosaccharides lies in the fact that the carbohydrates have to be non-reducing to yield products which
are easier to identify/characterize. For the preparation of non-reducing oligosaccharides we used the
approach of Tanaka et al.2 In here the authors show an effective method to yield glycosyl azides. In
that report, the obtained products were purified via preprative HPLC, we desired however a more
scaleable purification method. Standard silica gel chromatography turned out succesful for glucosyl
azide but not for higher oligosaccharides. In search of an effective way to purify oligosaccharides on a
preparative scale we studied charcoal column chromatography. Following the work of Whistler et al.,
we could sequentially elute different carbohydrates by employing a smooth gradient of ethanol/water.
With this effective purification method we were able to employ our method for the selective oxidation.
With 7.5 mol% of [(neocuproine)PdOAc]2OTf2 full conversion in the oxidation was obtained and we
could isolate the oxidized oligosaccharide pure and in good isolated yields. Identification of the
oxidation position was carried out using 2D-NMR techniques combined with mass fragmentation
studies. In all cases the terminal glucose residue was oxidized on the C3 position.
!
[1]
Jäger, M.; Hartmann, M.; Vries, J. G.; Minnaard, A. J. Angew. Chem. Int. Ed. 2013, 30, 7809–7812.
Tanaka, T.; Nagai, H.; Kobayashi, N. A.; Shoda, S. Chem. Comm., 2009, 23, 3378
[3]
Whistler, R. L.; Durso, D. F. J. Am. Chem. Soc. 1950, 72, 677–679
[2]
Protein labelling has played an important role in the area of biological chemistry1. Several approaches
both genetically and chemically were introduced by the scientific community. The introduction of so
called bioorthogonal groups into proteins is of high interest for the further study of these proteins in
vitro and in vivo. A rather promising method for the labelling in living systems are the ligand-directed
chemistries2. As an example, van Hest and co-workers3 showed the introduction of azide groups into
proteins by imidazole-1-sulfonyl azide. It was shown that the transfer takes place even in the absence
of the catalyst Cu(II) and at nearly physiological pH conditions. However, the transfer is rather
unspecific and a modification is to be expected at the N-terminus or any lysine ε-amine which is
exposed to the reagent and whose pKa is low enough to be deprotonated at a given pH.
In this study the directed chemical introduction of azido groups into proteins by conversion of amino
groups is shown. To this end, diazotransfer probes directed specifically towards a binding site of target
proteins were synthesized. Diazotransfer from probe to protein was monitored by the introduction of
an alkyne-bearing fluorophore into the protein, subsequent to diazotransfer making use of the Cu(I)
catalysed 1,3-dipolar cycloaddition between azides and terminal alkynes (click-chemistry). This
convenient and quick detection procedure allowed for the thorough evaluation of the compounds in
terms of activity and specificity even in a complex protein environment. Protein mass spectrometry
was used to confirm the introduction of the azide functionality and its efficiency.
1.
Sletten, E. M. & Bertozzi, C. R. Angew. Chem. Int. Ed. 48, 6974–6998 (2009).
2.
Takaoka, Y., Ojida, A. & Hamachi, I. Angew. Chem. Int. Ed. 52, 4088–4106 (2013).
3.
Schoffelen, S. et al. Chem. Sci. 2, 701 (2011).
Monodisperse oDMS-oLA block co-oligomers: Working on the
limits of block copolymer synthesis and self-assembly
Bas van Genabeek, Bas F. M. de Waal, Mark M. J. Gosens, Anja R. A. Palmans
and E. W. (Bert) Meijer
Bas van Genabeek, Het Kraneveld 4, 5612 AZ Eindhoven, Helix building STO 4.47
[email protected]
Diblock copolymers are perfect candidates to generate well-ordered systems with sub-100
nm feature sizes. Because of the broad application scope of such polymers, studies on the
self-assembly of these materials and the resulting microphase separated systems is
conducted by many research groups. Reducing the feature size and number of defects is
one of the focus points of this research. However, the possible consequences of chain length
dispersity and variation in polymer composition on the defect-less repeatability of the
nanoscale features are often neglected. Although some studies showed that this is
acceptable to do for copolymers in the intermediate dispersity regime (Ð = 1.05‒2.00),[1] truly
monodisperse systems (Ð = 1) have only be studied computationally. To bridge this
dispersity gap, and evaluate the limits of precision polymer synthesis and the segregation
behavior of a perfectly defined polymeric system, we developed a scalable synthesis route
for discrete length (i.e. monodisperse) diblock ‘co-oligomers’ based on dimethylsiloxane and
lactic acid monomers.[2-3] Using a iterative approach and orthogonal protective group
chemistry, we were able to obtain multigram quantities of monodisperse
oligodimethylsiloxane (oDMS) and oligolactic acid (oLA) blocks. A unique library of fully
monodisperse diblock co-oligomers with varying length and composition (DP = 25-50) was
finally obtained by careful ligation of both blocks.
References:
[1]
[2]
[3]
For a nice overview, see: N. A. Lynd; A. J. Meuler; M. A. Hillmyer. Prog. Polym. Sci. 2008, 33,
875.
H. Uchida; Y. Kabe; K. Yoshino; A. Kawamata; T. Tsumuraya; S. Masamune. J. Am. Chem.
Soc. 1990, 112, 7077.
K. Takizawa; H. Nulwala; J. Hu; K. Yoshinaga; C. J. Hawker. J. Polym. Sci. Part A Polym.
Chem. 2008, 46, 5977.
Fragment Linking of Inhibitors of the Aspartic Protease Endothiapepsin Facilitated by ProteinTemplated Click Chemistry
M. Y. Ünver,1 M. Mondal,1 A. Pal,1M. Bakker,1 S. Berrier,1 G. Klebe,2 A. K. H. Hirsch1
1
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen
2
Institut für Pharmazeutische Chemie, Philipps Universität Marburg, Marbacher Weg 6,
Marburg, Germany
Fragment-based design (FBD)1 enables the design of bioactive compounds. Whereas there are numerous
reports on FBD using optimization of a hit by fragment growing/optimization, fragment linking is rarely
used.2 Protein-catalyzed click chemistry is a hit-identification strategy, in which azides and alkynes are
assembled irreversibly to the corresponding triazoles.3
We have demonstrated that fragment linking and protein-templated click chemistry constitutes an
efficient hit-identification strategy. Using co-crystal structures of the aspartic protease endothiapepsin
and fragments,4 we have designed a library of inhibitors generated from alkynes and azides and used
protein-templated click chemistry to identify potent inhibitors, which were characterized by UPLCTOF/SIM.
References:
1. T. L. Blundell, H. Jhoti, C. Abell, Nat. Rev. Drug Discovery 2002, 1, 45–54.
2. P. J. Hajduk, G. Sheppard, D. G. Nettesheim, E. T. Olejniczak, S. B. Shuker, R. P. Meadows, D. H.
Steinman, G. M. Carrera, Jr., P. A. Marcotte, J. Severin, K. Walter, H. Smith, E. Gubbins, R.
Simmer, T. F. Holzman, D. W. Morgan, S. K. Davidsen, J. B. Summers, S. W. Fesik, J. Am. Chem.
Soc. 1997, 119, 5818–5827.
3. R. Manetsch, A. Krasinski, Z. Radic, J. Raushel, P. Taylor, K. B. Sharpless, H. C. Kolb, J. Am. Chem.
Soc. 2004, 126, 12809–12818.
4. H. Köster, T. Craan, S. Brass, C. Herhaus, M. Zentgraf, L. Neumann, A. Heine, G. Klebe, J. Med.
Chem. 2011, 54, 7784–7796.
Acyl hydrazone based dynamic combinatorial libraries
responsive to UV irradiation
I. Cvrtila, H. F. Virgós and S. Otto
Ivica Cvrtila, Centre for Systems Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
[email protected]
Photoswitchable receptors[1] present an efficient way to control binding and release of guest
molecules, both with respect to energy and materials needed. Dynamic combinatorial
chemistry, on the other hand, efficiently leads to discovery of new receptors.[2] The two
approaches above can be combined by including photoswitchable functionalities into building
blocks for dynamic combinatorial libraries, so to obtain receptors that can be switched on or
off.[3] In this research a slightly different approach is used, with the photoswitchable
functionality being the same as the one used for covalent exchange. Acyl hydrazone
chemistry is selected as the means of connecting the building blocks, since it provides
reversible covalent bonds, stability in water and, finally, easily photoswitchable double
bonds.[4] As the guest binding unit, a cyclen moiety is added, due to its ability to coordinate
metal cations and host various anionic guests. The pyridine dialdehyde building block further
increases the number of metal coordination sites, but also serves to stabilize the Z-form of
the hydrazone C=N bonds. Combined, these two building blocks may present a simple way
to obtain dynamic combinatorial libraries of photoswitchable molecules.
References:
[1]
[2]
[3]
[4]
M. Natali and S. Giordani, Chem. Soc. Rev., 2012, 41, 4010–4029.
F. B. L. Cougnon and J. K. M. Sanders, Acc. Chem. Res. 2012, 45, 2211–2221.
L. A. Ingerman and M. L. Waters, J. Org. Chem., 2009, 74, 111–117.
G. Vantomme, N. Hafezi ans J.-M. Lehn, Chem. Sci., 2014, 5, 1475–1483.
Analyzing dynamics in supramolecular polymers
Daan van der Zwaag, Lorenzo Albertazzi, Pascal A. Pieters, Tom F. A. De Greef,
E.W. Meijer
Daan van der Zwaag, Institute for Complex Molecular Systems, Eindhoven University of
Technology
[email protected]
Self-assembly is an efficient approach for the fabrication of nanostructured materials, with
the reversible interactions between building blocks providing self-healing and responsive
properties. In particular, one-dimensional supramolecular polymers show great promise in
the fields of nanoelectronics and biomedical engineering1. Recent work on the dynamics of
both natural2 and synthetic3 supramolecular polymers shows that a detailed understanding of
the kinetics of self-assembly is crucial for controlling functionality. Here, we outline different
approaches to extract this mechanistic information from kinetic experiments.
First, we investigated the aggregation of a bipyridine-extended benzenetricarboxamide
(BiPy) molecule through a combination of spectroscopy and numerical modeling.
Temperature and concentration dependent spectroscopic measurements showed two
aggregate signatures for BiPy, which warranted further investigation since the presence of
two assembly pathways can have a strong influence on the aggregation kinetics4. Thus, timeresolved temperature-jump spectroscopy was used in combination with ODE-based models
to elucidate the mechanistic details of the self-assembly process.
Additionally, super-resolution optical microscopy was explored as a means to observe the
exchange
dynamics
of
supramolecular
polymers
directly.
A
water-soluble
benzenetricarboxamide (BTA) derivative functionalized with switchable fluorescent labels
was studied using stochastic optical reconstruction microscopy (STORM), visualizing the
exchange of molecules between different aggregates5. By analyzing the distribution of
transferring molecules over time the mechanism of exchange could be unraveled,
demonstrating the use of STORM as a unique tool for the investigation of dynamics in
polymer materials.
References:
[1]
[2]
[3]
[4]
[5]
T. Aida et al., Science 2012, 335, 813-817
S.I.A. Cohen et al., Proc.Nat.Acad.Sci.USA 2013, 110, 9758-9763
S.Ogi et al., Nat.Chem. 2014, 6, 188-195
P.A. Korevaar et al., Nature 2012, 481, 492-496
L. Albertazzi et al., Science 2014, 344, 491-495
Poster Abstracts
There will be a Best Poster award kindly offered by TCI Chemicals.
You can vote for your favorite poster after the poster session, there will be a
dedicated box where you should leave your vote.
In the Search of Bigger Replicators from Dynamic
Combinatorial Libraries
Yiğit Altay and Sijbren Otto
University of Groningen, Center for Systems Chemistry, Stratingh Institute for Chemistry,
Nijenborgh 4, 9747 AG, Groningen, The Netherlands
[email protected]
One of the most fundamental questions at the interface between biology and chemistry is
what constitutes the minimal molecular basis of life. There is a big gap in our knowledge
considering the early steps of the formation of evolvable life. Systems chemistry, and
dynamic combinatorial chemistry in particular, is a promising approach to address this
intriguing question.
Figure 1. Schematic representation of self-replication in a dynamic combinatorial library.
Self-replicating systems constructed by β-sheet prone peptide building blocks, reported up
to day, formed hexamers and heptamers as the largest macrocycle size.1 Recent studies2
in our group showed that decreasing the hydrophobicity of the building blocks leads to
formation of larger macrocycles consisting of 8 building blocks. This study aims to further
extend the set of building blocks that can give rise to replicators having even larger
macrocycle size, consisting of 9, 10 or more building blocks. Among all the parameters, an
investigation of the hydrophobicity/hydrophilicity of the building blocks was chosen to
explore the size limits of replicating systems. If the β-sheet type interactions between the
building blocks are weakened, macrocycles having a larger number of building blocks will
be favoured to compensate this effect. In order to weaken the intermolecular interactions,
the hydrophobicity of the building blocks was decreased by incorporating more hydrophilic
amino acids (such as Asn, Thr) and phosphorylated amino acids. Furthermore, the Ctermini of the peptide building blocks were decorated with an amide functionality. The
resulting new sequences were synthesized and the replication behaviour of the dynamic
combinatorial libraries made from these building blocks is being investigated.
References:
[1]
J. M. A. Carnall; C. A. Waudby; A. M. Belenguer; M. C. A. Stuart; J. J.-P. Peyralans; S. Otto.
Science 327 (2010) 1502-1506.
[2]
M. Malakoutikhah; J.J.-P. Peyralans; M. Colomb-Delsuc; H. Fanlo-Virgós; M. C. A. Stuart; S.
Otto. J. Am. Chem. Soc. 135 (2013) 18406–18417.
Multicomponent Cascade Synthesis of Biaryl-based Chalcone
Derivatives in Pure Water and in Aqueous Micellar
Environment
Nicola Armenise, Danilo Malferrari, Sara Ricciardulli, Paola Galletti, Emilio
Tagliavini
Nicola Armenise, Via F. Selmi 2, 40126 Bologna, Italy
[email protected]
The goal of Green Chemistry is the design of chemical products and processes able to
reduce or avoid the handling and emission of hazardous materials. In particular, the
employment of solvents is highly concerning since it gives rise to toxicity, hazard and
pollution issues. In this context the employment of water as solvent has attracted much
interest in recent years. In fact, water offers many advantages because it is a cheap, readily
available, non-toxic and non-flammable solvent, thus being very attractive from both an
economical and an environmental point of view.
Among the organic reactions that can be conducted in water, cross-coupling and aldol
condensation reactions play an outstanding role; moreover, these kind of reactions can be
coupled together with one-pot and sequential procedures.
In particular, the one-pot synthesis of biarylchalcones in aqueous medium, through the
sequential Suzuki– Miyaura coupling and aldol condensation reactions, is a challenging but
attractive synthetic route. Unfortunately, the poor solubility of many substrates in water, the
formation of β-arylated ketones as side product and other drawbacks still limit the exploitation
of this strategy.
Looking for the sustainability of the synthetic processes, we have developed an highly
efficient protocol aimed to the multicomponent cascade synthesis of biaryl(hetero)chalcones
and of their functionalized derivatives, in pure water or in aqueous micellar system,
overcoming the existing drawbacks. The first step of our protocol is a simple Pd-catalyzed,
ligand-free and aerobic Suzuki-Miyaura reaction in aqueous medium, which has proved to be
extremely efficient for the coupling of aryl and heteroaryl bromides with different arylboronic
acids. The second step consists of the addition of the third substrate (ketone or aldehyde)
that undergoes in situ aldol condensation reaction.
When the protocol was applied to highly lipophilic or less reactive reagents, micellar catalysis
was required for achieving good performances. To this aim we successfully employed a new
surfactant that we recently designed from renewable resources. Furthermore, thanks to this
additive, the catalytic system could be repeatedly recycled without significant loss of activity.
[1]
Rajesh Kumar, Richa, Nitin H. Andhare, Amit Shard, and Arun K. Sinha, Chem. Eur. J. 2013,
19, 14798 – 14803
Towards Self-Replicating Molecules Capable of Forming
Compartments
Boris Bartolec, Jianwei Li, Giulia Leonetti, Sijbren Otto
Boris Bartolec, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
[email protected]
The idea that life on Earth originated from inanimate matter via a series of chemical steps of
increasing molecular complexity and functionality has been widely accepted in scientific
community. However, the transition from non-living to living state is hard to conceive both
from experimental and conceptual point of view. The important step in this direction is to
design a chemical system in which essential requirements for life (replication, metabolism
and compartmentalization) are integrated.
Investigating the emergence of compartments (compartmentalization) made from selfreplicating molecules (replication) from a network of interconverting molecules (a primitive
form of metabolism) is a way to fabricate such a chemical system.
Such network can be created by the Dynamic Combinatorial Chemistry (DCC) approach
where reversible covalent reactions are used to link building blocks together, forming libraries
of compounds whose product distribution is under thermodynamic control. Addition of a
template results in the shift of the equilibrium, amplifying those library members that are
stabilized by the template. Amplification may also occur in the absence of a template: if one
or more species in the library can self-assemble, the library composition will favor those
species that can form the most stable aggregates. When the self-assembled species are
further amplified by the self-replication and they consist of compartments, the system in
which compartmentalization is driven by self-replication is achieved.
Figure 1. Different combinations of superchemical though infrabiological
subsystems, inspired by Ganti’s general scheme of the chemoton, based on
three coupled autocatalytic cycles: template (T), metabolic (M), and
boundary (B) subsystems. The TMB ternary supersystem would already
1
meet all the requirements for life.
[1]
K. Ruiz-Mirazo, C. Briones, A. de la Escosura, Chem. Rev. 2014, 114, 285−366.
Controlling enzyme activity through artificial allostery
Manuela Bersellini, Gerard Roelfes
Manuela Bersellini, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747AG Groningen, The Netherlands
[email protected]
Allostery is the control of enzymatic activity via an effector molecule that causes a structural
change in a protein resulting in a change of catalytic activity. The design of artificial allosteric
systems is an emerging field as they are of great interest due to their application as sensors,
in drug delivery and drug targeting [1].
Previously, we have reported a split artificial allosteric enzyme based on DNA-conjugated
split murine Dihydrofolate Reductase (mDHFR). DNA hybridization was used as the driving
force to mediate the reassembly of the split enzyme into a catalytically active conformation
[2].
Currently, we aim to use supramolecular interactions to direct the reassembly of the split
enzyme. In one approach, DNA-receptor conjugates with sequences complementary to the
protein linked oligonucleotides are used and the simultaneous binding of a guest molecule to
both receptors will cause the reassembly of the split enzyme. Also, metal coordination is
used to reassemble the split enzyme. Metal binding unnatural amino acid (2,2’-bipyridin5yl)alanine and 2-amino-3-(8-hydroxyquinolin-3-yl)propanoic acid are introduced at the
extremities of each mDHFR fragment by in vivo incorporation [3].
Small molecule (left) and metal coordination (right) controlled split enzyme
An alternative strategy to introduce allosteric control in proteins is using mechanical strain,
introduced by DNA hybridization or metal coordination. In this study we aim to develop an
artificial allosteric protease.
[1]
[2]
[3]
[4]
Goodey N. M., Benkovic S. J., Nat. Chem. Biol., 2008, 8 474.
Sancho Oltra N., Bos, J., Roelfes, G., ChemBioChem, 2010, 11, 2255.
Lee, H. S., Spraggon, G., Schultz, P. G. & Wang, F. J. Am. Chem. Soc., 2009, 131, 2481–
2483. Xie, J., Liu, W. & Schultz, P. G., Angew. Chem. Int. Ed. 2007, 46, 9239–9242.
B. Choi, G. Zocchi, J. Am. Chem. Soc. 2006, 128, 8541
Bioorthogonal Metal Catalysis
A. Dowine de Bruijn, Gerard Roelfes
Dowine de Bruijn, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
[email protected]
The possibility to target specific biomolecules in living systems via bioorthogonal reactions
have greatly increased our knowledge of the behaviour of biomolecules in their natural
environment[1,2,3]. Mostly via the introduction of a small chemical handle like azide, alkyne or
aldehyde it is possible to introduce fluorescent labels without interference with native
biochemical processes. However these reactions are mainly stoichiometric and/or require the
introduction of two different bioorthogonal groups for one labeling event. We therefore
envisioned that labeling of a naturally occurring chemical handle like dehydroalanine (Dha)
will significantly increase the utility of bioorthogonal reactions. Dha is the product of the posttranslational dehydration of serine[4]. It contains an electron deficient terminal alkene which is
receptive towards chemical reactions. When Dha is catalytically modified in vivo,
biosynthesis is combined with unnatural chemistry to give access to novel molecular
structures.
In this project we use the terminal alkene of Dha as substrate for the oxidative Heck
reaction[5]. Pd(EDTA)Cl2 is used as water soluble catalyst[6], which is inexpensive and readily
available. Modification of a single Dha-unit was successfully performed in vitro, without the
addition of oxidising agent to regenerate Pd(II) from Pd(0). The modification of Dha as
subunit of a protein by the same catalytic reaction will be discussed.
[1]
[2]
[3]
[4]
[5]
[6]
Prescher, J.A. and Bertozzi, C.R., Nat. Chem. Biol., 2005, 1, 13
Ramil, C.P. and Lin, Q., Chem. Comm., 2007, 49, 11007
Yang, M., Li, J. and Chen, P.R., Chem. Soc. Rev., 2014, 43, 6511
Knerr, P.J. and Van der Donk, W.A., Annu. Rev. Biochem., 2012, 81, 479
Karimi, B., Behzadnia, H., Elhamifar, D., Akhavan, P.F., Esfahani, F.K. and Zamani, A.,
Synthesis, 2010, 9, 1399
Ourailidou, M.E., Dockerty, P., Witte, M., Poelarends, G.J. and Dekker, F.J, Org. Biomol.
Chem., 2015, 13, 3648
G-quadruplex-based surfactants
Liliana Cozzoli, Lorina Gjonaj, Gerard Roelfes
Liliana Cozzoli, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747AG Groningen,The Netherlands
[email protected]
Recently, there has been a growing interest towards the development of DNA-based
materials, especially for their applications in nanotechnology[1] and drug delivery.[2]
The ability of oligonucleotides to self-assemble make them a promising scaffolds for the
design of complex supramolecular structures with accurate control over their composition,
structure and functions.
It has been shown that lipid-functionalized oligonucleotides in aqueous solution
spontaneously self-assemble into micellar nanostructures with a lipid core and a DNA
corona, while retaining the molecular recognition properties of DNA.[3] Because of their small
size, biocompatibility, high stability and the ability to improve the solubility of hydrophobic
drugs, this kind of nanostructures are of great interest for biomedical application.
In this work, we synthesized a new class of surfactants through conjugation of several
lipophilic tails with short guanine-rich DNA sequences. In the presence of cations, such as
K+, the DNA folds into a parallel G-quadruplex bringing the four hydrophobic tails in proximity
and forming the surfactants. These modified G-quadruplexes self-organize and assemble in
nanostructures like micelles or fibers, depending on the specific structural characteristics.
Moreover, the planar structure formed by the G-quadruplex can accommodate selectively
small molecules or ligands. We have investigated the interaction the G-rich-based micelles
with a cationic porphyrin, showing that the interaction was possible while still preserving the
structural integrity of the micelles.
[1]
[2]
[3]
Zhang, F.; Nangreave, J; Liu, Y; Yan, H; J. Am. Chem. Soc., 2014, 136, 11198-11211
Zhang, Q.; Jiang, Q.; Li, N.; Dai, L.; Liu, Q.; Song, L.; Wang, J.; Li, Y; Tian, J.; Ding, B.; Du,
Y.; ACS Nano, 2014, 8, 6633–6643
Liu, H.; Zhu, Z.; Kang, H.; Wu Y.;, Sefan K.; Tan W.; Chem. Eur. J., 2010, 16, 3791-3797
Acyl hydrazone based dynamic combinatorial libraries
responsive to UV irradiation
I. Cvrtila, H. F. Virgós, S. Otto
Ivica Cvrtila, Centre for Systems Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
[email protected]
Photoswitchable receptors[1] present an efficient way to control binding and release of guest
molecules, both with respect to energy and materials needed. Dynamic combinatorial
chemistry, on the other hand, efficiently leads to discovery of new receptors.[2] The two
approaches above can be combined by including photoswitchable functionalities into building
blocks for dynamic combinatorial libraries, so to obtain receptors that can be switched on or
off.[3] In this research a slightly different approach is used, with the photoswitchable
functionality being the same as the one used for covalent exchange. Acyl hydrazone
chemistry is selected as the means of connecting the building blocks, since it provides
reversible covalent bonds, stability in water and, finally, easily photoswitchable double
bonds.[4] As the guest binding unit, a cyclen moiety is added, due to its ability to coordinate
metal cations and host various anionic guests. The pyridine dialdehyde building block further
increases the number of metal coordination sites, but also serves to stabilize the Z-form of
the hydrazone C=N bonds. Combined, these two building blocks may present a simple way
to obtain dynamic combinatorial libraries of photoswitchable molecules.
[1]
[2]
[3]
[4]
M. Natali, S. Giordani, Chem. Soc. Rev., 2012, 41, 4010–4029.
F. B. L. Cougnon, J. K. M. Sanders, Acc. Chem. Res. 2012, 45, 2211–2221.
L. A. Ingerman, M. L. Waters, J. Org. Chem., 2009, 74, 111–117.
G. Vantomme, N. Hafezi, J.-M. Lehn, Chem. Sci., 2014, 5, 1475–1483.
Novel artificial metalloenzymes by in vivo incorporation of
metal-binding unnatural amino acids
Drienovská I., Roelfes G.*
Ivana Drienovská, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747 AG Groningen, [email protected]
Artificial metalloenzymes are hybrids of homogeneous and enzymatic catalysts. They
combine the high activity and selectivity of enzymatic catalysis with the versatility of
organometallic catalysts. The most common approaches for creating artificial
metalloenzymes involve covalent or supramolecular anchoring of the synthetic
ligand/transition metal catalysts to the host protein[1]. Here, we introduce a novel strategy that
comprises in-vivo incorporation of a metal-binding unnatural amino acid (2,2΄bipyridin5yl)alanine (Bpy-Ala) into the protein[2].
The transcription factor LmrR (Lactococcal multidrug resistance Regulator), which contains a
hydrophobic pocket at the dimer interface was chosen as the host protein scaffold[3]. Three
positions, Asn19, Met89 and Phe93 located inside the hydrophobic pocket, were mutated to
incorporate the unnatural amino acid Bpy-Ala. Upon binding of Cu2+, the resulting artificial
metalloenzyme was capable of catalyzing several types of reactions, including Friedel-Crafts
and water addition reactions with moderate enantiomeric excess[4]. A mutagenesis study was
performed to identify essential residues for catalysis and further enhance conversion and
enantiomeric excess of the reactions.
References
[1]
[2]
[3]
[4]
F. Rosati, G. Roelfes, ChemCatChem 2010, 2, 916-927.
J. Xie, W. Liu, P.G Schultz, Angew. Chem. Int. Ed. 2007, 46, 9239-9242.
P.K. Madoori, H. Agustiandari, A.J.M. Driessen, A. W. H. Thunnissen, EMBO Journal 2009,
28, 156-166.
I. Drienovská, A. Rioz-Martínez, A. Draksharapu, G. Roelfes, Chem. Sci, 2014, 6, 770-776.
Selective modification of unprotected oligosaccharides
!
Niek N. H. M. Eisink, Martin D. Witte, Adriaan J. Minnaard
!
Niek Eisink, Stratingh Institute, University of Groningen, Nijenborgh 7,
9747 AG Groningen, The Netherlands
[email protected]
Selective modification of unprotected carbohydrates is a relatively unexplored area, with the
exception of the modification of the primary hydroxyl group and the anomeric center. Such
modifications on oligosaccharides are scarce and furthermore seldom involve one of the
secondary hydroxyl groups. In the field of chemical biology, where often more complex
carbohydrates are employed, selective modifications are highly desired. Recently, in our
group we have developed an effective procedure for the regioselective oxidation of monoand disaccharides.1 With this method, we can selectively oxidize the C3 hydroxyl group on
the terminal glucose residue in maltose and cellobiose. The formed ketone moeity opens up
a whole range of further modifications of these carbohydrates. We envisioned that we could
apply the same method to modify higher oligosaccharides. A boundry in applying our method
for oligosaccharides lies in the fact that the carbohydrates have to be non-reducing to yield
products which are easier to identify/characterize. For the preparation of non-reducing
oligosaccharides we used the approach of Tanaka et al.2 In here the authors show an
effective method to yield glycosyl azides. In that report, the obtained products were purified
via preprative HPLC, we desired however a more scaleable purification method. Standard
silica gel chromatography turned out succesful for glucosyl azide but not for higher
oligosaccharides. In search of an effective way to purify oligosaccharides on a preparative
scale we studied charcoal column chromatography. Following the work of Whistler et al., we
could sequentially elute different carbohydrates by employing a smooth gradient of
ethanol/water. With this effective purification method we were able to employ our method for
the selective oxidation. With 7.5 mol% of [(neocuproine)PdOAc]2OTf2 full conversion in the
oxidation was obtained and we could isolate the oxidized oligosaccharide pure and in good
isolated yields. Identification of the oxidation position was carried out using 2D-NMR
techniques combined with mass fragmentation studies. In all cases the terminal glucose
residue was oxidized on the C3 position.
!
[1]
[2]
[3]
Jäger, M.; Hartmann, M.; Vries, J. G.; Minnaard, A. J. Angew. Chem. Int. Ed. 2013, 30, 7809–
7812.
Tanaka, T.; Nagai, H.; Kobayashi, N. A.; Shoda, S. Chem. Comm., 2009, 23, 3378
Whistler, R. L.; Durso, D. F. J. Am. Chem. Soc. 1950, 72, 677–679
Bio-orthogonal metalloporphyrin catalysts for in vivo
chemistry
Ruben Maaskant, Gerard Roelfes
Ruben Maaskant, Stratingh Institute for Chemistry, University of Groningen
[email protected], [email protected]
In recent years the development of synthetic metal complexes for in vivo chemical
transformations has received much attention, using these complexes as catalyst for nonbiological reactions [1]. Whereas these metal complexes were used for the labelling of
biomolecules by cross-coupling or protecting group cleavage [2,3], they could also be
employed for in vivo synthesis. By adding a new reaction to the ‘toolbox’ already available to
nature, new pathways could be opened and new chemical structures can be obtained from
biosynthesis.
A range of metal complexes, for example metalloporphyrins, can be used for in vivo
transformations. Porphyrins have been shown to be biocompatible and their localization in
cells can be controlled [4].
Figure 1
In this project, metalloporphyrins will be synthesized and employed in catalysis of
cyclopropanations and aziridinations of dehydroalanine in living cells (Figure 1).
References:
[1]
[2]
[3]
[4]
P.K. Sasmal, C.N. Streu, E. Meggers, Chem. Commun. 2013, 49, 1581–1587.
S.V. Chankeshwara, S.V., E. Indrigo, M. Bradley, Curr. Opin. Chem. Biol. 2014, 21, 128-135
C. Streu, E. Meggers, Angew. Chem. Int. Ed. 2006, 45, 5645-5648
I. Batinic-Haberle, L. Benov, I. Spasojevic, I. Fridovich, J. Biol. Chem. 1998, 273, 24521-24528
Palladium-Catalyzed Conjugate Addition of Aryl iodides to
Activated Alkenes
Subramaniyan Mannathan, Johannes G. de Vries, Adriaan J. Minnaard
Subramaniyan Mannathan, Stratingh Institute for Chemistry, Nijenborgh 7,
9747AG Groningen
[email protected]
Transition-metal catalyzed conjugate addition of organometallic reagents to activated
alkenes is one of the efficient methods to form C-C bonds in organic synthesis. A variety of
organometallic reagents such as organoboron, -zinc, -aluminium, -silicon, and magnesium
(Grignard) reagents have been used and these strategies are well documented. On the other
hand, application of aryl iodides in these types of reactions has been rarely studied. Herein,
we present a palladium catalyzed conjugate addition of aryl iodides to activated alkenes [1].
As compared to our previously reported effective Pd(0)-NHC catalyst system [2], this method
provides an opportunity to use a relatively inexpensive palladium catalyst with similar
efficacy.
R2
I
R1
EWG
1 mol% Pd(OAc) 2
DIPEA (5.0 equiv)
NMP, 80 °C, 6 h
R1
EWG
R2
upto 80% yield
R1
R2
= Aryl, alkyl
EWG = COR, NO 2
= OMe, Cl, F, CF 3
12 examples
After careful optimization of the reaction conditions, various activated alkenes have been
examined. Enones are the most effective substrates affording 1,4-addition products in good
yields. Interestingly, β-nitrostyrenes also work well, furnishing the conjugate addition
products in moderate yield. On the other hand, reactions with acrylates and unsaturated
nitriles, give solely the corresponding Heck products. A variety of aryl iodides has been
applied to give the corresponding 1,4-addition products in good yield.
[1]
[2]
S. Cacchi, A. Arcadi, J. Org. Chem. 1983, 48, 4236–4240
A. L. Gottumukkala, J. G. de Vries, A. J. Minnaard, Chem. Eur. J. 2011, 17, 3091–3095.
DNA-based catalytic cyclopropanation in water
Ana Rioz-Martínez, Jens Oelerich, Gerard Roelfes
Ana Rioz-Martínez, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
[email protected]
DNA-based asymmetric catalysis represents a powerful tool for the preparation of chiral
compounds in water [1]. This novel concept is based on the use of hybrid catalysts, which
comprise a transition metal complex bound to DNA. In this way, the reaction occurs in close
proximity to the DNA, allowing chirality transfer and subsequent formation of one of the
enantiomers of the reaction product [2]. These hybrid catalysts have been exploited in many
Lewis acid catalytic enantioselective reactions [1]. Recently, the catalytic scope of DNA-based
catalysis has been expanded beyond Lewis acid catalysis when it was applied successfully
in a Cu(I) catalysed intramolecular cyclopropanation of α-diazo-β-keto sulfones [3]. This
promising example demonstrates that carbene chemistry is compatible with DNA and
encouraged us to explore an improved catalytic system and expand the reaction scope of
DNA-based catalysis. Iron porphyrins have been applied in several cyclopropanations in
water [4] and cationic porphyrins are well known ligands that can bind through π-stacking and
electrostatic interactions to DNA [5]. In this work, we discovered a DNA-based catalytic
cyclopropanation in water catalysed by iron porphyrin/salmon testes DNA hybrids.
Additionally, it was found that the reaction was highly accelerated in the presence of DNA.
[1]
[2]
[3]
[4]
[5]
A. J. Boersma, R. P. Megens, B. L. Feringa, G. Roelfes, Chem. Soc. Rev. 2010, 39, 20832092.
G. Roelfes, B.L Feringa, Angew. Chem. Int. Ed. 2005, 44, 3230-3232.
J. Oelerich, G. Roelfes, Chem. Sci. 2013, 4, 2013-2017.
B. Morandi, E.M. Carreira, Science. 2012, 335, 1471-1474.
V. Pradines, G. Pratviel, Angew. Chem. Int. Ed. 2013, 52, 2185-2188.
Selective Fuctionalized Iron Oxide Nanoparticles' Surface
Based on Dynamic Imine Chemistry in The Presence of
Biotemplate
Xiaoming Miao, Piotr Nowak, Sijbren Otto
Xiaoming Miao, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
[email protected]
Molecular recognition plays a quite important role in biological systems such as
receptor-ligand recognition, antigen-antibody recognition, and RNA-ribosome. With these
accurate recognition processes, organisms can live and develop exquisite function, adaption
and evolution, etc. Unlike the molecular recognition in synthetic systems, most of molecular
recognition in biological systems involve macromolecular interactions. Currently, research is
increasingly focusing on the interaction and recognition between biological functional
macromolecule such as protein-protein interactions (PPI). Some new insights into processes
central to life can be obtained through these studies, it also can contribute to find new lead
compounds in the process of drug discovery.
Dynamic Combinatorial Chemistry (DCC) is an excellent method for achieving molecular
recognition. DCC is a method of generating new molecules by reversible reaction of simple
building blocks under thermodynamic control[1]. Here, DCC will be used for the surface
functionalization of nanoparticles aiming at the recognition of the surface of
biomacromolecules, such as DNA[2] and protein. Aldehyde groups will be introduced on the
iron oxide nanoparticles which are reacted with amines to produces a dynamic combinatorial
nanoparticles surface through reversible imine bond formation in water solution. In the
presence of biomacromolecules, surface functionalization should be selective for those
amines that have affinity for the biomacromolecules. The labile imine bonds may then be
reduced to stable amines, resulting in nanoparticles which have a surface complementary to
the biomacromolecules. Such nanoparticles should then be able to interfere with proteinprotein interactions in biological systems and may become useful tools for biochemical
studies and may even have therapeutic potential.
[1]
[2]
Corbett, P.T., J. Leclaire, L. Vial, et al., Chem. Rev., 2006, 106, 3652-3711.
Nowak, P., V. Saggiomo, F. Salehian, et al., Angew. Chem. Int. Ed., 2015, 54, 4192-4197.
Beyond the affinity for the protein kinase C: a critical
evaluation of 2-phenyl-3-hydroxypropyl pivalate analogues
targeting the C1 domain
Rita Nasti, Annamaria Marra, Gustav Boije Af Gennäs, Virpi Talman, Jari YliKauhaluoma, Raimo K. Tuominen, Jeewoo Lee, Daniela Rossi, Simona Collina
Rita Nasti, University of Pavia, Department of Drug Sciences,
Via Taramelli 12, 27100 Pavia, Italy
[email protected]
In the last fifteen years, numerous compounds having as target the C1 domain of protein
kinase C were projected and synthetized1. Among those, our attention was focused on
compound 1, which emerged as potent and promising PKCα ligand (K1= 0.7 µM) (fig 1). On
the base of this template, thirteen novel analogues were designed and synthetized to better
understand which structural modifications are allowed to preserve the affinity for C1 domain
of PKC and their interaction was evaluated in silico.
HO
O
O
Bn
BnO
HO
O
O
HO
O
Which structural changes
are allowed?
O
R1
R2
compound 1
- Benzyl ester
- N methyl N benzyl
- N,N-dyetilamine
- Morpholine
4-OBenziloxy
3-OBenziloxy
4-Phenyl
Fig.1
We prepared and fully characterized all compounds and their affinity for α and δ isoforms of
PKC was evaluated. It has to be noted that some compounds, in particular those having
benzyl ester moieties, have a poor chemical stability. For the most interesting PKC ligand,
the role of chirality in the ligand-target interaction was investigate. Taken together, results of
biological assays clearly indicate that only few chemical structure modifications are allowed
in such series of compounds and that the C1 domain of PKC doesn’t exhibit
enantiopreference for the pure stereoisomers of tested compounds. 2
[1]
[2]
Baba, Y.et al. Bioorg. Med. Chem. Lett. 2004, 14, 2963-2967.-Marquez V.E et al Acc. Chem.
Res. 2003, 36, 434.- Kang, J.-H et al.Org. Lett. 2004, 6, 2413.-Boije af Gennäs G et al J.
Med. Chem., 2009, 52, 3969–3981-Lee, J.et al Bioorg. Med. Chem. 2006, 14, 2022-2031.
Rossi, D et al. Med.Chem.Comm. 2015, 6, 547-554
Supramolecular Assembly of Artificial Metalloenzymes for
Enantioselective Protonation
Lara Villarino Palmaz, Gerard Roelfes
Lara Villarino Palmaz, Stratingh Institute for Chemistry, Nijenborgh 4, Groningen, 9747AG,
The Netherlands
[email protected]
Artificial metalloenzymes are hybrid catalysts in which a catalytically active transition metal
complex is incorporated into a host biomacromolecule, typically a protein or DNA. The aim is
combine the best of both worlds, that is, broad catalytic scope, a hallmark of homogeneous
catalysis, and high activity and selectivity under mild conditions, which typically characterizes
enzymatic catalysis.[1]
The key parameter in artificial metalloenzymes design is the second coordination sphere
provided by the biomolecular scaffold. The Roelfes group developed a novel concept for the
creation of artificial metalloenzymes, which involves the creation of an active site in the dimer
interface of the transcription factor “Lactococcal multidrug resistance Regulator” (LmrR). A
copper(II)-phenantroline complex was anchored in the hydrophobic pocket of the protein
using a cysteine conjugation strategy. This new metalloenzyme was successfully employed
in the catalytic asymmetric Diels-Alder reaction, with up to 97% ee, [2] and in the conjugate
addition of water, with up to 84% ee.[3]
Supramolecular assembly of the transition metal complex is very attractive, since the hybrid
catalyst is prepared by self-assembly. Thus, there is no need for chemical modification and
subsequent purification steps, which greatly facilitates the discovery, optimization and
application of novel artificial metalloenzymes. Herein, we present the supramolecular
assembly of a novel artificial metalloenzyme based on LmrR and its application in a highly
challenging reaction: the tandem Friedel Crafts/Enantioselective protonation in water
(Scheme 1). [4]
Scheme 1
References:
[1] F. Rosati, G. Roelfes, ChemCatChem, 2010, 2, 916-927.
[2] J. Bos, F. Fusetti, A. J. M. Driessen, G. Roelfes, Angew. Chem. Int. Ed, 2012, 51, 7472-7475.
[3] J. Bos, A. García-Herraiz, G. Roelfes, Chem. Sci., 2013, 4, 7472-7475.
[4] J. T. Mohr, A. Hong, B. M. Stoltz, Nature Chem., 2009, 1, 359-369.
hiral
y
etry
reakin
by
yntheti
epli ators
Xinkai Qiu, Wietse Smit, Piotr Nowak and Sijbren Otto
Stratingh Institute for Chemistry, Centre for Systems Chemistry, The Zernike Institute for Advanced
Materials
e-mail: [email protected]
Life is homochiral, but the origin of its homochirality from the achiral environment still remains as
one of the biggest scientific challenges. One hypothesis suggests that small enantiomeric excess
(ee) could lead to an amplification of chirality in a self-replicating system.[1]
Replication can be achieved using self-assembled mechanosensitive fibers.[2] Such fibers
can easily amplify initial chiral information (SS principle).[3] In our system, chiral self-replicating
fibers compete for the chiral 1-2 adduct, formed from achiral building blocks (Fig. 1). The
formation of the adduct is reversible, providing a recycling mechanism.
We observed that initially racemic systems deracemized over time. We hypothesize that
homochiral fibers selectively incorporate a preferred 1-2 enantiomer, replicate through growth
and fragmentation cycles, while the fibers composed of the minor enantiomer are recycled.
Transfer of chiral information between molecular and supramolecular levels is efficient, as
shown by the correlation between ee measurements and CD signal.
Fig. 1. Schematic representation
of fiber formation by adduct 1-2
and two proposed deracemization
pathways.
[1] J.S. Siegel, Chirality 1998, 10:24-27.
[2] J.M.A. Carnall, C.A. Waudby, A.M. Belenguer, M.C.A. Stuart, J.J.-Peyralans, S. Otto, Science 2010,
327, 1502-1506.
[3] a) A.R.A. Palmans, J.A.J.M. Vekemans, E.E. Havinga, E.W. Meijer, Angew. Chem. Int. Ed. Engl.
1997, 36, 2648-2651. b) D.J. van Dijken, J.M. Beierle, M.C.A. Stuart, W. Szamanski, W.R. Browne, B.L.
Feringa, Angew. Chem. Int. Ed. 2014, 53, 5073-5077.
New Artificial Metalloenzyme Containing an Iron Coordinating
Active Site
Nathalie Ségaud, Apparao Draksharapu, Wesley Browne, Gerard Roelfes
Nathalie Ségaud, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747AG Groningen, The Netherlands
[email protected]
One of the major current challenges is to develop sustainable approaches to chemical
synthesis. The power of chemical and biological synthesis can be merged by integrating nonnatural synthetic chemistry into bio-synthetic pathways. By developing novel artificial
metalloenzymes and incorporating them into cells, sustainable synthesis of molecules with
novel structural features that are difficult to achieve in any other way could be achieved.[1]
This will result in novel building blocks that can be used as pharmaceutical intermediates, or
complex molecules with novel or enhanced biological activity, such as antibiotics.
A new approach to artificial metalloenzymes was reported recently by our group,[2] which
comprises of a new active site in the hydrophobic pocket of the dimeric protein LmrR. This
active site is composed of covalently anchored phenanthroline or bipyridine ligands at a
specific position (figure 1).
Figure 1. Left, Space filling structural representation of LmrR with phenanthroline
ligands anchored ; right, anchoring of phenanthroline and bipyridine ligands to LmrR.
In the context of oxidation catalysis that mimics peroxidases, we report here a study of the
iron complexes formed with this new artificial protein.
[1]
[2]
Thomas CM, Ward TR. Chem. Soc. Rev. 2005, 34, 337-346.
(a) Bos J, García-Herraiz A, Roelfes G. Chem. Sci. 2013, 4, 3578-3582.
(b) Bos J, Fusetti F, Driessen AJM, Roelfes G. Angew. Chem. Int . Ed. 2012, 124, 7590–7593.
Design and Length Control of Mixed Block Co-fibers From
Dynamic Combinatorial Libraries
Meniz Tezcan, Sijbren Otto
University of Groningen, Center for Systems Chemistry, Stratingh Institute Chemistry,
Nijenborgh 4, 9747AG, Groningen, Netherlands
[email protected]
Self-replicating systems play a very important role both in origin of life and material science
in which the assembly process strongly affects the resulting properties of the material[1]. In
such supramolecular assemblies it is very challenging to precisely control the structure and
dimensions of resulting self-synthesizing material that grows on nuclei. Very recently, in our
group, it has been shown that, controlled self-assembly with homogeneous seeds having
certain lengths help to achieve a control over resulting fiber lengths with the living property of
nucleation-growth process[2].
Figure 1. a) Mechanism of self-replicating fibers in a dynamic combinatorial library. b) Peptide replicators used in
design and lenght control of mixed block co-fibers.
In this study, it has been tried to extend the scope of living nature of peptide replicators
through the formation of B-A-B type triblock co-fibers with controlled length. In order to
achieve this, two different hexamer forming peptide replicators have chosen for the block
compositions. The food mixture (3mer/4mer of outer blocks) has been seeded with hexamer
seeds of the inner block. Formation of the supramolecular assemblies has been confirmed by
partially reducing the fiber ends and sample composition is followed on UPLC as the amount
of reducing agent is gradually changed.
References:
[1] J. M. A. Carnall, C. A. Waudby, A. M. Belenguer, M. C. A. Stuart, J. J.-P. Peyralans and S. Otto,
Science, 2010, 327, 1502-1506.I. A. M. A. Chemist, Research Notes 2007, 1, 5–7.
[2] A.Pal, M. Malakoutikhah, G. Leonetti, M. Tezcan, M.C. Delsuc, V.D. Nguyen, J.V.D. Gucht, S.
Otto., submitted.
Workweek Committee
Yiğit Altay
[email protected]
Meniz Tezcan
[email protected]
Ruben Maaskant
[email protected]
Bonte Avond Committee
Nabil Tahiri
[email protected]
Gongbao Wang
[email protected]
Alwin Hartman
[email protected]
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